This invention was discovered during the process development work on efavirenz (1), a non-nucleoside reverse transcriptase inhibitor currently being sold under the trademarks Stocrin .TM. (registered trademark of Merck & Co., Inc.) and Sustiva.TM. (registered trademark of DuPont Pharmaceuticals Company). A practical synthesis of efavirenz has been developed, based upon asymmetric alkynylation chemistry, which has been implemented for large scale manufacture [a) M. E. Pierce, R. L. Parsons, Jr., L. A. Radesca. Y. S. Lo, S. Silverman, J. R. Moore, Q. Islam, A. Choudhury, J. M. D. Fortunak, D. Nguyen, C. Luo, S. J. Morgan, W. P. Davis, P. N. Confalone, C. Chen, R. D. Tillyer, L. Frey, L. Tan, F. Xu, D. Zhao, A. S. Thompson, E. G. Corley, E. J. J. Grabowski, R. Reamer, P. J. Reider, J. Org. Chem., 1998, 63, 8536-8543. b) Recently, an efficient, protection free process was reported: L. Tan, C. Chen, R. D. Tillyer, E. J. J. Grabowski, P. J. Reider, Angew. Chem. Int. Ed., 1999, 38, 711-713.].
In defining the synthesis of 1, two options were evaluated for conversion of protected propargyl alcohols 2a/2b into the final 1,4-dihydro-2H-3,1-benzoxazin-2-one product. The first involved deprotection of the amino alcohols 2a/2b to give 3, which was reacted with phosgene or with p-nitrophenylchloroformate to give 1. The alternative approach involved ring closure to give the N-protected carbamates 4a or 4b, followed by deprotection. While one of the first routes (p-methoxybenzyl [PMB] protection) was developed into the manufacturing process, investigation of the ring closure reaction of trityl protected propargyl alcohol 2a [M. E. Pierce, et al., J. Org. Chem., 1998, 63, 8536-8543.]uncovered this novel rearrangement chemistry and ring systems.